A Response Calculus for Immobilized T Cell Receptor Ligands

Abstract

To address the molecular mechanism of T cell receptor (TCR) signaling, we have formulated a model for T cell activation, termed the 2D-affinity model, in which the density of TCR on the T cell surface, the density of ligand on the presenting surface, and their corresponding two-dimensional affinity determine the level of T cell activation. When fitted to T cell responses against purified ligands immobilized on plastic surfaces, the 2D-affinity model adequately simulated changes in cellular activation as a result of varying ligand affinity and ligand density. These observations further demonstrated the importance of receptor cross-linking density in determining TCR signaling. Moreover, it was found that the functional two-dimensional affinity of TCR ligands was affected by the chemical composition of the ligandpresenting surface. This makes it possible that cellbound TCR ligands, despite their low affinity in solution, are of optimal two-dimensional affinity thereby allowing effective TCR binding under physiological conditions, i.e. at low ligand densities in cellular interfaces. Most T cells present ␣␤ T cell receptors (TCR)1 on their surface. The natural ligands for these receptors are small antigenic peptides bound to MHC molecules (pep⅐MHC) on the surface of other cells with which T cells interact (1). Antigen recognition can result in various protective functions, including release of cytokines to cause local inflammation and specific killing of virus-infected cells (2).The TCR comprises the ␣/␤ subunits that recognize pep⅐MHC and the signal-transducing subunits ␦, ⑀, ␥, and (CD3-complex), which contain the immunoreceptor tyrosinebased activation motifs (ITAMs) (3). Signaling of the TCR⅐CD3-complex can be viewed as a dynamic phosphorylation/dephosphorylation equilibrium of ITAMs where the steady-state levels of phosphorylated ITAMs are low in unstimulated T cells (4). The molecular mechanism by which ligand-bound TCR perturbs this equilibrium is unknown.One way to help identify the molecular features underlying TCR signaling is to develop mathematical models capable of simulating TCR signaling. Describing TCR signaling as a dynamic equilibrium indicates that it should be possible to model T cell behavior using mathematical expressions involving the binding constants of TCR⅐ligand interactions. Moreover, as recently discussed (5), such models are attractive because they allow for simulation of T cell responses and thus help guide future research, and because they can assist in optimizing clinical immunomodulatory strategies.Previous mathematical analysis of T cell responses have been successful in modeling specific features such as fast ligand dissociation kinetics (6), peptide antagonism (7, 8), rate of receptor internalization (9), or the effect of co-stimulation on proliferation (10). Current models favor a discrimination between the potency of TCR ligands based on the life-time of the interaction, i.e. the off-rate (6, 7, 9). In Support, recent studies suggest that TCR signaling correlates to ligand disso...

The Stalk Domain and the Glycosylation Status of the Activating Natural Killer Cell Receptor NKp30 Are Important for Ligand Binding

“…Human melanoma cells (MelJuSo) were kindly provided by E. Wiertz (31). Ba/F3 cells transduced with B7-H6 (Ba/F3-B7-H6) or the empty vector (Ba/F3-mock) were provided by C. Watzel (IfADo, Germany), and A5 cells were kindly provided by A. Diefenbach (32).…”

Homo-oligomerization of the Activating Natural Killer Cell Receptor NKp30 Ectodomain Increases Its Binding Affinity for Cellular Ligands

“…Ba/F3 cells transduced with B7-H6 (Ba/F3-B7-H6) or the empty vector (Ba/F3-GFP) were kindly provided by C. Watzl (IfADo) and cultivated as described (43). Murine A5 T cell hybridoma cells (CD4 ϩ ) transduced with retrovirus encoding full-length NKp30 fused to a C-terminal decahistidine tag (A5-30FL-His) or a mock control (A5-GFP) were kindly provided by A. Diefenbach (University of Freiburg, Germany) (34,44).…”

Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells

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